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Upper airway resistance syndrome
Sleep Medicine
Reviews, Vol. 3, No. 1, pp 5-21, 1999
SLEEP MEDICINE pGj
REVIEW ARTICLE
Upper airway J. M . Montserrat
resistance
syndrome
and J. R. Badia
Servei de Pneurnologia i Al.ltrgia Respirathia, Departament de Medicina, Hospital Clinic, Facultat de Medicina de la Universitat de Barcelona, Barcelona, Spain
This article reviews the clinical picture, diagnosis and management of the upper airway resistance syndrome (UARS). Presently, there is not enough data on key points like the frequency of UARS and the morbidity associated with this condition. Furthermore, the existence of UARS as an independent sleep disorder and its relation with snoring and obstructive events is in debate. The diagnosis of UARS is still a controversial issue. The technical limitations of the classic approack to monifor airflow with tkermistors and inductance pletkysmograpky, as well as the lack of a precise definition of kypopnea, may have led to a misinterpretation of UARS as an independent diagnosis from the sleep apnea/hypopnea syndrome. The diagnosis of tkis syndrome can be missed using a conventional polysomnograpklc setting unless appropriate techniques are applied. The use of an esophageal balloon to monitor inspiratory effort is currently the gold standard. However, other sensitive methods suck as the use of a pneumotackograpk and, more recently, nasal cannula/pressure transducer systems or on-line monitoring of respiratoy impedance witk the forced oscillation technique may provide other interesting possibilities. Recognitiofl and characterization of tkis subgroup of patients within sleep breathing disorders is important because tkey are symptomatic and may benefit from treatment. Management options to treat UARS comprise all those currently available for sleep apnea/kypopnea syndrome ISAHS). However, the subset of patients classically identified as UARS that exhibit skeletal craneo-facial abnormalities might possibly obtain further benefit from maxillofacial surgery. Key words: obstructive
sleep apnea, OSAS, SAHS, UARS, flow limitation
In the last decades the existence of sleep disordered breathing, its clinical consequences and its high prevalence have been progressively recognized and can be considered a major health problem [l]. Initially, attention focused on the sleep apnea through studies of the classical picture of the Pickwick syndrome that involved a group of obese patients with respiratory and cardiovascular co-morbidity that presented with a large number of apneas during sleep. However, progressively, our concept of sleep disordered breathing has substantially changed since the description of the Pickwickian syndrome. The spectrum of sleep disordered breathing is today much broader and ranges from non-apneic situations, such as simple snoring and hypopnea, to obstructive sleep apnea. In fact, with the description by the group of Douglas, that airflow reduction or hypopnea due to partial collapse promoted the same disturbances as complete
Correspondence to be addressed to: J. M. Montserrat, Servei de Pneumologia i Al.krgia Respiratbria, Hospital Clinic, Villarroel170,08036 Barcelona, Spain. e-mail: [email protected] 1087-0792/99/010005+17$12.00/0
0 1999 W.B. Saunders Company
Ltd
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J. M. Montserrat and J. R. Badia
apnea [2], the terminology “sleep apnea/hypopnea syndrome” (SAHS) has become the most appropriate to quantify events in sleep disordered breathing. Patients with SAHS suffer repeated episodes of increased upper airway resistance with partial or complete collapse that lead to profound disturbances in sleep architecture and arterial blood gases [3,4]. Repeated inspiratory efforts occur during obstructive events until arousal ensues and airway patency is restored [5]. Repeated arousals and sleep fragmentation are responsible for subsequent daytime sleepiness. Increases in upper airway resistance, the main pathophysiological feature of SAHS, are not exclusive to apnea and hypopnea and may also be present in simple snoring and in other entities like the topic of this review: the upper airway resistance syndrome. In this respect, we believe that the main pathophysiological features that take place in the upper airway resistance syndrome (UARS) are similar to those in hypopnea. The obstructive events that occur in SAHS are secondary to an increased upper airway collapsibility. Indeed, in apneas the critical opening pressure, which is the minimal intraluminal pressure required to maintain upper airway patency, increases above atmospheric pressure during sleep. As a consequence, a static occlusion occurs and apnea takes place. On the other hand, during hypopneas, the intraluminal pressure is just above the critical opening pressure. In this situation, the inspiratory effort decreases intraluminal pressure below the critical opening pressure, the upper airway collapses partially and the inspiratory flow becomes limited. Figure 1 shows three examples of the spectrum of airflow obstruction ranging from complete apnea (Fig. la) to hypopnea with marked airflow limitation (Fig. lb, c). Depending on the magnitude of this dynamic upper airway obstruction ventilation may be reduced substantially (hypopnea) or slightly (UARS). These changes may not be recognized if the devices used to analyse and quantify airflow are not sensitive enough. In this context it is clear that the most widespread palliative treatment applied in SAHS, nasal CPAP, has a double function: on the one hand it prevents the static obstruction (CPAP pressure overcomes critical opening pressure) and on the other hand, CPAP should be able to compensate for the maximum inspiratory dynamic collapse, thus avoiding hypopneas and the UARS. Lugaresi has reported very high inspiratory pressures in heavy snorers below the fluttering segment [6]. Taking into account that snoring is the major symptom associated with SAHS, this author proposed a unitary explanation, an evolving continuum from snoring to obstructive events and apnea [7]. He suggested a theory of a snoring scale and “snoring disease”, in which snoring represented the stage 0 of obstructive sleep apnea syndrome. Christian Guilleminault had the merit to clarify, at least in part, the relationship between increased respiratory resistance, snoring and sleep fragmentation with daytime sleepiness providing a further insight into this complex situation. In 1982, this author provided an initial report on the effect of increased respiratory load during sleep in children with symptoms similar to that of sleep apnea [8]. Along this line he identified heavy snoring as a cause of excessive daytime sleepiness [9]. This author and co-workers reassembled the conception of sleep disordered breathing with the description of the upper airway resistance syndrome (UARS) [lO,ll]. They focussed their attention on a group of subjects with complaints of excessive daytime sleepiness (EDS) presenting with a trivial number of obstructive events as currently scored during full polysomnography. Sleep fragmentation with short repetitive arousals secondary to increased upper airway resistance in the absence of apnea and hypopnea were observed and were related to EDS. Some of the patients had maxilo-mandibular abnormalities. Reversal of sleep fragmentation and sleepiness was achieved with nasal continuous positive airway pressure (nCPAP) further supporting the evidence that
Upper airway
resistance syndrome
7
(a)
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1. Examples of the three different patterns of oscillatory airway impedance during respiratory events. Pattern (a) corresponds to an apnea with a corresponding persistent increase of 1Z ( o b served throughout the apnea. Patterns (b) and (c) depict two different hypopneas with minimal airflow and the corresponding intermittent patterns in 1Z I. In the first hypopnea (b), high Z values are interrupted by intermittent decreases during expiration whereas pattern (c) shows normal 1Z ( values, followed by intermittent increases during inspiration. (Reproduced with permission from Badia R. et al. Eur Respir J 1998.) Figure
abnormal upper airway resistance was responsible for the disorder. Furthermore, the relation between snoring, UARS and SAHS has become even more intriguing with the description of UARS in subjects that do not snore [11,12]. To date, the frequency of UARS in snorers and non-snorers as well as the morbidity associated with this condition are still unknown. Depending on the methodology applied to diagnose the syndrome, UARS may be significantly under-recognized. It may even be possible that UARS is
J. M. Montserrat and J. R. Badia
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Figure 2. (a) Actual flow measured by the pneumotachogarph (V’) for sinusoidal airflows of 1 l/s and 0.5 l/s for a square-wave flow of 0.5 l/s (peak-to-peak). (b) Thermistor signal (V’th) recorded simultaneously. (Reproduced with permission from Farre R. et al Eur Respir 1 1988.) not an independent disorder from hypopneas but, a subgroup with particular identifiable traits in the spectrum of SAHS that needs appropriate technology to be diagnosed. In fact, the use of thermistors as flow-measuring devices for detecting hypopneas has been recently questioned [13]. Farre et al. assessed the accuracy of thermistors/thermocouples as devices for detecting hypopneas in sleep studies. These authors demonstrated that the thermistors were strongly nonlinear and largely underestimated flow reductions. A 50% reduction of the real flow resulted in only an 18% reduction in the thermistor signal. The example in Figure 2 clearly shows that the thermistor is not able to accurately measure the real flow or reproduce the morphology of the inspiratory flow. Therefore, the use of thermistors to quantify hypopneas may lead to considerable underdetection of respiratory periods of increased upper airway resistance. Another technical aspect is the concept of the morphology of the inspiratory flow as a simple and easy way to detect increases in upper airway resistance. In common with other colleagues, we have introduced nasal prongs connected to a pressure transducer as a better tool to measure ventilation [14-191. This method offers two advantages: (1) if the square root of the signal is used, then the signal is reliable from the quantitative point of view; and (2) owing to the accuracy of this signal, flow limitation can be identified without the use of an esophageal balloon. Therefore, we have proved that nasal prongs are more sensitive than thermistors in quantifying ventilation [17-191. All the previous considerations suggest that UARS probably represents a subgroup of patients within sleep disordered breathing that demand a more accurate technology. Unless a sensitive monitoring methodology is used, this condition may be missed. These patients are symptomatic because they have sleep disordered breathing-related arousals, but these respiratory events are not detected by thermistors. To recognize these particular events technologies other than thermistors are needed. In most cases
Upper airway resistance syndrome
9
appropriate use of the sum of the thoracoabdominal movement, the nasal prongs or a pneumotachograph will allow in the recognition of sleep related arousals secondary to periods of upper airway obstruction, avoiding the use of an esophageal balloon. The SAHS and the UARS have common features; similar symptoms, same pathophysiology with increased upper airway resistance and large negative esophageal pressures, increased number of arousals. Finally, both conditions improve with nCPAI? However, SAHS and the UARS differ substantially in the results of the full polysomnography. Specifically, UARS presents EDS in the absence of respiratory events (as defined using thermistors) and with minimal or absent oxygen desaturation.
Definition
and clinical
picture
The initial definition of UARS included the combination of three criteria: (1) a complaint of daytime sleepiness documented or not with a multiple sleep latency test; (2) demonstration of short repetitive periods of flow limitation by monitoring esophageal pressure (Pe,); and (3) periods of increased respiratory efforts with arousal following peak negative inspiratory I’,, [ll]. Figure 3 shows an example from the original description by Guilleminault et al. [l]. Please note that increases in I’,, as well as airflow limitation are present in the cycles prior to arousal. The common clinical picture of UARS is that of a subject with prominent symptoms of excessive daytime sleepiness and a conventional polysomnographic sleep study with a trivial respiratory disturbance index (RDI). Dips in oxygen saturation are minimal and, frequently, not present at all. Unless invasive procedures are used increased respiratory efforts remain unnoticed. Daytime sleepiness, the guiding sign of UARS, is due to repeated arousals and sleep fragmentation [10,12]. Snoring, a hallmark of SAHS, is not always present. In contrast to SAHS, individuals are frequently slim. They may also exhibit mild mandible defects or evident retrognatia associated with an abnormally narrow ogival hard palate. Narrow posterior airway space at the base of the tongue in cephalometric studies has also been described as possibly a common feature [11,20,21]. Whereas SAHS is diagnosed much more frequently in males, the incidence of UARS seems to be similar in both genders. All these distinctive traits provide a characteristic profile that can help in the recognition of UARS. Although scattered, there seems to be enough information to establish a clinical picture of the syndrome. Unfortunately, solid data on the prevalence and significance of each of these features in UARS is completely missing and the diagnosis requires polysomnography (PSG) data as well as the demonstration of increased respiratory resistance leading to sleep fragmentation. UARS is still very difficult to identify and the morbidity beyond EDS related with this condition remains largely unknown. Despite the current suggestion that increased upper airway resistance may lead to systemic hypertension and cardiovascular disorders [22-241 morbidity has not been characterized. This is not surprising and is possibly related to the uncertainty of the diagnosis of UARS itself. Prospective studies that rely on more accurate definitions are needed. The question again is whether UARS has a definite identity distinct from SAHS and if it may exist in the absence of hypopneas or apneas. The methodology applied in the diagnosis of UARS is a core issue. It is possible that, in addition to the use of an esophageal balloon, new and more sensitive technologies which are available to monitor airflow obstruction, will contribute to unravel the real significance and incidence of this condition.
J. M. Montserrat and J. R. Badia
ECG
Figure 3. Original picture by C. Guilleminault et a2. of a PSG recording showing an example of upper airway resistance syndrome. Key: EEG, electroencephalogram; EMG~~,,i,l, facial muscle electromyogram; EOG, electrooculogram (right and left); ECG, electrocardiogram; Flow rneumotach, pneumotachometer to quantify airflow; I’,,, esophageal manometry to record esophageal pressure; RESP,,,, respiratory effort. Please note that increases in I’,, as well as airflow limitation are present in the cycles prior to a transient EEG arousal indicated by the solid arrowhead (Reproduced with permission from Guilleminault C. et al. Chest 1993.)
Diagnostic
strategy
The conventional PSG approach fails to recognize the UARS. Thus, the diagnosis of UARS has required monitoring of I’,, with an esophageal balloon to identify periodic increases in inspiratory effort. It seems likely that these result from increases in airway resistance secondary to airflow obstruction, although this may be subtle or limited to very short periods. Again, the methodology applied to monitor airflow appears critical. The use of an esophageal catheter to monitor inspiratory effort as an indirect measure of airflow obstruction is the gold standard. When using I’,, the most distinctive trait is not the isolated values of negative inspiratory pressure itself but the characteristic pattern of progressive fast decrease of I’,, that abruptly returns to normal, or almost normal, after a neurological arousal. However, the procedure is invasive and can
Upper airway
resistance
syndrome
11
influence the measure [25]. Other confounding issues are the interindividual variability of the values of P,, and the variability related to changes in sleep phase as well as the need to establish the range of normal values. Measurement of P,, with an esophageal catheter probably cannot be recommended as a diagnostic routine. In most laboratories changes in nasal and mouth airflow ventilation are currently detected and measured by thermally sensitive devices -thermistors[26]. Indirect parameters, such as thoracic and abdominal movements measured with bands, are also reliable [2]. Depending on the qualitative changes in the thermistor signal and thoraco-abdominal motion apneas and hypopneas are defined. However, hypopneas are still a matter of controversy. Scoring depends much on the recording technique and a precise definition of hypopnea is completely lacking [27]. In this respect, the accuracy of thermistors/thermocouples as flow-measuring devices for detecting hypopneas is far from optimal [13,28,29]. As previously pointed out, they are semiquantitative devices since the flow signal they provide is not a direct measure of actual flow. Thermistors have a very poor time response and show a critical dependence on the airflow pattern, the distance to the nose and the cross-section of the nostrils. These drawbacks do not produce major problems to score apneas. However, the use of thermistors to quantify hypopneas leads systematically to underdetection of these respiratory events. If thermistors are used we can assume that the respiratory disturbance index (RDI) in hypopneic patients is underestimated. In addition, short periods of flow limitation leading to arousal or microarousal can be completely overlooked. It is possible that if we use an esophageal catheter a substantial number of these patients may meet criteria to label them as UARS. The importance of developing a non-invasive methodology that allows precise monitoring of airflow obstruction is obvious. It is necessary to use techniques capable of detecting subtle changes in airflow. An attractive option can be the regular use of a pneumotachograph. However, to acquire a flow signal with a pneumotachograph a tight-fitting nasal or face mask is required. More recently, it has been suggested that nasal cannula or prongs connected to a pressure transducer could be a useful alternative to monitor respiratory events due to their ability to measure and quantify nasal flow [14]. The main advantage of nasal prongs is their good dynamic response when compared with thermistors. Our group conduct e d a study to evaluate if nasal prongs could improve the detection of respiratory-related arousals and respiratory events [18]. Nasal prongs proved to be much more sensitive than thermistors and thoraco-abdominal bands and the detection of respiratory events increased significantly (from 62% with thermistors to 96% with nasal prongs) In addition, the number of false positives related to mouth expiration was reasonable (3%). Figure 4 is a good example of the poor accuracy of thermistor to recognize respiratory events compared with nasal prongs. We also found that nasal prongs were easily tolerated during sleep studies even when applied together with thermistors. An additional advantage of these devices is their ability to detect airflow characteristics due to their excellent dynamic response. The upper airway behaves as a Starling resistor and, in conditions of increased resistance due to partial collapse, inspiratory airflow has a nonlinear relation with inspiratory esophageal pressure. Increases in inspiratory effort do not generate a further increase in flow. When an adequate measurement of actual flow is available it has been shown that limitation in the inspiratory waveform is correlated with elevated upper airway resistance and increased esophageal pressure [15,16]. Partial airflow limitation can be identified by a flattened morphology of the inspiratory flow contour. Figure 5 (a-c) show the higher accuracy of nasal prongs to recognize respiratory events and their ability to provide
J. M. Montserrat and J. R. Badia
C4-Al
O-A EMG-GG
EMG legs
.__._-___I
.._.-- ---.
-..-- --_ --._- “--
-___._ __
SaO,
Figure 4. A representative polysomnographic view of the behavior of nasal prongs during hypopneas. Note the poor detection of respiratory events obtained through thermistors. Respiratory events are much more clearly identified by nasal prongs. Key: EOG, electrooculogram; EMG-GG, electromyogram; ECG, electrocardiogram. information on flow limitation. Please note that in these examples the thermistor is completely unable to detect the changes that take place in ventilation. Figure 6 (a) and (b) shows the accuracy of nasal prongs to detect airflow limitation and the relation with esophageal pressure and upper airway resistance. Nasal prongs/pressure transducer systems have additional advantages, as the detection of snoring (Fig. 5a) or a more precise follow-up of the time-course of respiratory events within the breathing cycle. Nevertheless, nasal prongs may present some problems, for example the inability to detect mouth expiration or the possible occurrence of physiological flow limitation in normal subjects [30]. The role of nasal prongs in everyday work in the sleep laboratory is still not well defined. Criteria to score respiratory events or definition of physiological changes in this signal need further research and standardization. However, these systems provide a valuable and complementary diagnostic tool. We have already included the use of nasal prongs in our routine diagnostic setting. In our experience since we have implemented this signal, the number of patients that may fit in the definition of UARS has dramatically decreased. This further supports the concept that UARS may be, at least in part, a “technical” syndrome directly related to a suboptimal methodology to measure and quantify airflow obstruction. Another diagnostic approach to non-apneic situations with subtle changes in respiratory variables is to monitor upper airway impedance by means of the forced oscillation technique. The forced oscillation technique (FOT) provides a non-invasive method to assess and quantify airway obstruction. It consists in superimposing on the spontaneous breathing a small pressure oscillation through a nasal mask attached to the patient [31]. Respiratory impedance (Z) is derived on-line from pressure and flow signals recorded at the nasal mask. The potential applicability of FOT to assess airway obstruction in SAHS
Upper airway
resistance syndrome
13
has been confirmed in a model study [32]. In this preliminary work the amplitude of the impedance ( 1Z ( ) measured by FOT was found to be an accurate index of overall airflow obstruction. Our group has also evaluated the suitability and accuracy of the technique in diagnostic sleep studies in SAHS [33]. Figures 1 and 7 are examples of the clinical application of this technique to assess airflow obstruction both in apnea and hypopnea. The clinical applicability of FOT to assess airflow obstruction in real time during CPAP treatment has also recently been demonstrated in a limited number of patients with recording of I’, [34]. Figures 8 and 9 show the ability of FOT to recognize airflow obstruction during CPAI? This technique proved to be sensitive to even slight increases in upper airway resistance demonstrated by esophageal catheter in patients treated with slightly suboptimal CPAP and can improve detection of respiratory events inpatients with suspected UARS [35]. In our experience continuous measurement of airflow obstruction by FOT provides a very rational non-invasive approach to monitor airway mechanics and may allow a better characterization of non-apneic sleep disordered breathing. Pulse transit time (PTT) [36] and beat to beat blood pressure profile [36] can also be considered. These promising methods may detect increased respiratory effort and neurological activation (either arousal, microarousal or autonomic arousal), the two main components involved in the pathophysiology of UARS. However, further research on these procedures is needed to assess sensitivity and specificity in the detection of increased upper airway resistance before they can be introduced in standard diagnostic procedures.
Treatment UARS is still an undefined clinical situation. The main end points of treatment for abnormal increases of airway resistance should be to relieve symptoms and improve quality of life. The aim in treatment should be to reduce morbidity and mortality. However, in non-apneic situations as the classical description of UARS associated morbidity and mortality are far from determined. From a clinical perspective, treatment of increased upper airway resistance should alleviate snoring and daytime somnolence and, probably, the existence of associated cardiovascular morbidity should be considered in the final decision. Management options available to treat UARS comprise all those currently available for SAHS including weight loss, sleep posture, oral appliances, conventional CPAP and surgical procedures [38]. The first step in the management of these patients should possibly be to test general measures of weight loss and sleep positional treatment. There are no reliable data concerning weight loss and UARS. Although most patients are not obese, weight loss has a strong influence on snoring and upper airway collapsibility [39] and a first therapeutic attempt must be made. Positional treatment seems to have a higher impact on frequency and intensity of snoring, related with upper airway resistance, than on RDI itself [40] and should possibly be tested in combination with weight loss in this population. Dental malocclusion is a common feature in UARS. Oral appliances, in particular mandibular advancing devices, seem a good option to counteract increased upper airway resistance. However, there are no data available on this at the present time. CPAP must also be considered. Reversal of sleep fragmentation and daytime sleepiness is achieved. In our experience subjects with UARS appear to require a lower pressure than those with more severe obstructive events. However, there is some evidence suggesting that the compliance with CPAP could be unsatisfactory in these
J. M. Montserrat
14
5(a)
Thermistor
SaOz
5(b) EOG-I EOG-D
and J. R. Badia
Upper airway resistance syndrome
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5(c) EOG
--4--------p.
Snore
Figure 5. Three representative polysomnographic views of the behavior of nasal prongs during hypopneas. Note the null detection of respiratory events obtained through thermistors. A respiratory event could be missed if thermistor were the sole method used to detect airflow. The nasal prongs show a limited inspiratory flow (a, b), very short in (c), and an inspiratory vibration (a) that corresponds to snoring, ending with an arousal.
patients although results from different groups are at variance in this point [41,42]. A therapeutic trial with CPAP is a good choice in those symptomatic patients that do not improve on conservative treatment. Finally, surgical management must be considered. Published studies on surgery for UARS present general limitations that have been described in detail elsewhere [43]. Simple snorers and non-apneic subjects with increased upper airway resistance syndrome are more likely to obtain benefit from surgery than other patients. However, information on objective results is particularly scarce in this group and further studies are most needed [38,43]. In UARS skeletal abnormalities that may increase upper airway resistance are often present. Dental malocclusion and elevated ogival hard palate as well as a narrow posterior airway space seem to be, in our experience, common findings. Maxillofacial surgery aimed towards correcting upper airway skeletal anatomic abnormalities yield the best results of surgery in the treatment of SAHS and is probably the most rational approach for symptomatic patients in this subgroup [44-46]. Selection criteria and elucidation of predictive factors for this type of surgery need to be established.
Conclusion In our opinion the group of patients defined as having the upper airway resistance syndrome form a particular population within the spectrum of SAHS but not an
J. M. Montserrat and J. IL Badia
16 (a)
Nasal prongs
Thoracoabdominal
Esophageal
bands
pressure
(b)
EMG
EKG
Nasal prongs
P,,, (cmH@) -30OCfl Sa02
Figure 6. Representative tracings of respiratory variables and esophageal pressure during a sleep study. Note that periods of flow limitation correspond to high inspiratory esophageal pressure. Conversely, when esophageal pressure is low [during an arousal in (b)] the inspiratory flow morphology is rounded.
Upper airway resistance syndrome
Figure 7. A representative standard compressed polysomnographic recording (6 epoch, 3 min) with oscillatory impedance 1Z 1 added at the bottom. Note that 1Z 1 shows low values during arousal and increases during the apnea periods. The last event on this tracing corresponds to hypopnea. This increase shows cyclical variation before the onset of each apnea and during an hypopnea (last event in this figure). Definition of abbreviations according to channels: Electrooculogram (EOG) (channel #1 and #2); C4-Al and C3-A2 (electroencephalogram channels #3 and #4); chin electromyogram (EMG-GG) (channel #5); flow by pneumotacograph (channel #6); Effort: thoracicabdominal bands (channels #7 and #8); (Reproduced with permission from Badia et al. Eur Respir J 1988.) independent sleep disorder. In this sense, the real significance of UARS has probably been overestimated due to limitations of the methodology used to monitor airflow. This technical deficiency underlies the definition of this condition itself. Therefore, introduction of more sensitive devices will have a direct impact on the frequency and signification of this diagnosis. However, we do believe that there is a specific population, classically identified as UARS, that shares some features uncommon to the rest of subjects with SAHS. Possibly the most representative characteristic of this subgroup is the presence of a subtle respiratory dysfunction that is enough to generate arousal and sleep fragmentation and, therefore, daytime symptoms. Our knowledge of the functional properties of the upper airway that determine the appearance of snoring, hypopneas or apneas is still very limited. Furthermore, not much is known about the individual threshold at which increased upper airway resistance can elicit arousal, microarousal or autonomic arousal. Differences in these issues could explain the description of UARS without snoring in some cases or upper airway collapse at low inspiratory pressures in other subjects. A consensus on diagnostic methodology considering the new available technologies is required. A more accurate technical approach to sleep disordered breathing, in particular in non-apneic situations, will probably lead to a reconsideration of our current nosological definitions.
J. M. Montserrat and J. R. Badia
SaO,
Figure 8. A representative standard compressed polysomnographic recording obtained during CPAP titration with oscillatory impedance (Z ( added at the bottom. (Z ( shows intermittent increases at suboptimal CPAP corresponding with a limited inspiratory airflow morphology. Note that when CPAP is increased the shape of the inspiratory flow wave becomes rounded and values of 1Z 1 are similar to those obtained during awake normal breathing.
CPAP = 4 cmHzO
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30
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Figure 9. Breathing flow (V’), esophageal pressure (P,J and respiratory resistance (R,,) measured by the FOT in -a patient at different levels of CPAl? (Reproduced with permission from Navajas D. et al. Am J Respir Crit Cure Med. 1988.)
Upper airway resistance syndrome
19
Practice Points Upper airway resistance syndrome &JARS) is currently defined as the combination of: 1. excessive daytime sleepiness. 2. periods of increased respiratory effort terminating abruptly with an arousal without a major decrease in airflow when is measured by thermistor, and 3. without a significant fall in oxygen saturation The use of thermistors to asses flow may lead to considerable underdetection of respiratory events. Nasal prongs or a pneumotachograph or even the sum of thoracoabdominal motion improves the recognition of sleep related arousals secondary to periods of upper airway obstruction, avoiding the use of an esophageal balloon in many cases. When these signals are implemented in routine practice, hypopneas are accurately recognized and the number of patients diagnosed of UARS decreases dramatically. New more sensitive technologies available to monitor airflow obstruction will contribute to uncover the real significance and incidence of UARS. Research Agenda 1. Morbidity associated with non-apneic sleep disorders has not beeri established. Prospective studies that rely on more accurate definitions are needed 2. There is a specific population, classically identified as UARS, that shares some features uncommon to the rest of subjects with SAHS. A better characterization is needed. 3. Knowledge of the functional properties of the upper airway that determine the appearance of snoring, hypopneas or apneas and the individual threshold at which increased upper airway resistance can elicit arousal, microarousal or autonomic arousal is still very limited. 4. Long-term compliance with CPAP therapy irt patients with non-apneic sleep disorders needs further evaluation. 5. Selection criteria and elucidation of predictive factors for maxillo-facial surgery need to be established.
Acknowledgements This study was supported by Fondo de Investigaciones Sanitarias (FIS) no. 97/422 and FUCAP 97. References 1 Phillipson EA. Sleep apnea. A major public
health
problem.
1271-1273.
*The most important
references are denoted
with an asterisk.
N.Engl
J Med 1993; 328:
20
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and J. R. Badia
* 2 Gould GA, Whyte KF, Rhind GB, Airlie MAA, Catterall JR, Shapiro CM, and Douglas NJ. The sleep hypopnoea syndrome. Am Rev Respir Dis 1988; 137: 895-898. * 3 Remmers JE, DeGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. 1 Appl Physiol 1978; 44: 931-938. 4 White PD. Pathophysiology of obstructive sleep apnoea. Thorax 1995; 50: 797-804. 5 Kimoff RJ, Cheong TH, Olha AE, Charboneau M, Levy RD, Cosio MG, Gottfried SB. Mechanisms of apnoea termination in obstructive sleep apnoea: role of chemoreceptor vs mechanoreceptor stimuli. Am J Respir Crit Care Med 1994. 149: 707-714. 6 Lugaresi E, Farnetti Cl’, Mantovani M, Cirignotto F. Snoring. Electroencephalograph Clin Neurophysiol 1975; 39: 5964 * 7 Lugaresi E, Mondini S, Zuccani M, Montagna P, Cirignotta F. Staging of heavy snorers disease: a proposal. Bull Europ Physiopathol Respir 1983; 19: 590-594. 8 Guilleminault C, Winkle R, Korobkin R, Simmons B. Children and nocturnal snoringevaluation of the effects of sleep related resistive load and daytime functioning. Eur J Pediatr 1982; 139: 165-171. * 9 Guilleminault C, Stoohs R, Duncan S. Snoring (I). Daytime sleepiness in regular heavy snorers. Chest 1991; 99: 4048. *lO Guilleminault C, Stoohs R, Clerk A, Simmons J, Labanowski M. From obstructive sleep apnea syndrome to upper airway resistance syndrome: consistency of daytime sleepiness. Sleep 1992; 15: S13-S16. *ll Guilleminault C, Stoohs R, Clerk A, Cetel M, Maistros I? A cause of excesive daytime sleepiness. The upper airway resistance syndrome. Chest 1993; 104: 781-787. *12 Philip l’, Stoohs R, Guilleminault C. Sleep fragmentation in normals: a model for sleepiness associated with upper airway resistance syndrome. Sleep 1994; 17: 242-247. *13 Farre R, Montserrat JM, Rotger M, Ballester E, Navajas D. Accuracy of thermistors and thermocouples as flow-measuring devices for detecting hypopneas. Eur Respir J 1998; 11: 179-182. 14 Montserrat JM, R Far& E Ballester, M Felez, M Past6 and D Navajas. Evaluation of nasal prongs for estimating nasal flow. Am J Respir Crit Care Med. 1997; 155: 211-211. 15 Montserrat JM, Ballester E, Olivi H, Reolid A, Lloberes I’, Morello A, Rodriguez-Roisin R. Time-course of stepwise CPAP titration. Behaviour of respiratory and neurological variables. Am J Respir Crit Care Med 1995; 152: 1854-1859. 16 Condos R, Norman RG, Krihnasamy I, Peduzzi N, Goldring RM, Rappoport DM. Flow limitation as a noninvasive assessment of residual upper airway resistance during continuous positive airway pressure therapy of obstructive sleep apnea. Am J Respir Crit Care Med 1994; 150: 475480. 17 Norman RG, Ahmed MM, Walsleben JA, Rapoport DM. Detection of respiratory events during NPSG: nasal cannula/pressure sensor versus thermistor. Sleep 1997; 20: 1175-1185. 18 Ballester E, JR Badia, L Hernandez, R Far+, D Navajas, JM Montserrat. Nasal prongs in the detection of sleep related disordered breathing on the sleep apnea hypopnea syndrome. Eur Respir J 1998; 11: 880-883. 19 Hosselet JJ, Norman RG, Ayappa I, Rapoport DM. Am J Crit Care Med 1998; 157: 1461-1467. 20 Guilleminault C, Stoohs R, Clerk A, Simmons J, Labanowski M. Excessive daytime somnolence in women with abnormal respiratory efforts during sleep. Sleep 1993; S137-5138. 21 Guilleminault C, Stoohs R, Kim Y, Chervin R, Black J, Clerk A. Upper airway sleepdisordered breathing in women. Ann Intern Med 1995; 122: 493-501. 22 Guilleminault C, Suzuki M. Sleep related hemodynamics with partial or complete upper airway obstruction during sleep. Sleep 1992;15: S20-S24. 23 Guilleminault C, Stoohs R, Shiomi T, Kushida C, Schnittger I. Upper airway resistance syndrome, nocturnal blood pressure monitoring, and borderline hypertension. Chest 1996; 109: 901-908. 24 Silverberg DS, Oksenberg A. Essential hypertension and abnormal upper airway resistance during sleep. Sleep 1997; 20: 794-806. 25 Cala SJ, Sliwinsky P, Cosio MG, Kimoff RJ. Effect of topical upper airway anesthesia on apnea duration through the night in obstructive sleep apnea. J Appl Physiol 1996; 81: 2618-2626. 26 Parisi RA, Santiago TV, Respiration and respiratory function: technique of recording and evaluation. In: Chocroverty S. (ed.) Sleep Disorders Medicine. Basic Science, Technical Considerations and Clinical Aspects. Boston: Butterworth-Heinemann 1994; pp 127-133.
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27 Moser NJ, Philips BA, David TR, Berry PhD, Harbison L. What is hypopnea anyway? Chest 1994; 105: 426428. 28 Xiong C, Sjoberg BJ, Svelder P, Ask P, Loyd D, Wranne B. Problems in timing of respiration with nasal thermistor technique. J Am Sot Eckocardiogv 1995; 18: 330-333. 29 Past6 M, FGlez MA, Gea J et al. The efficiency of thermocouples in measuring hypopneas. Eur Respiv I 1995; 8 (Suppl. 19:253S). *30 Rappoport DM, Norman RG. Inspiratory flow limitation (FL) and sleep fragmentation in normal subjects. Am J Respir Cvit Cure Med 1995; 151: A153. 31 Peslin R, Fredberg JJ. 1986. Oscillation mechanics of the respiratory system. In: Handbook of Physiology. Vol 3, Part I. Bethesda, MD: American Physiology Society. 145-179. 32 Far& R, Peslin R, Rotger M, Navajas D. 1997. Inspiratory dynamic obstruction detected by forced oscillation during CPAI? A model study. Am ] Respir Crit Care Med. 155: 952-956. 33 Badia JR, Far& R, Montserrat, JM, Ballester E, Hernsndez L, Rotger M, Rodriguez-Roisin R, Navajas D. Forced oscillation technique for the evaluation of severe sleep apnoea/ hypopnoea syndrome: a pilot study. Eur Respir 1 1998; 11: l-7. 34 Navajas D, Farre R, Rotger M, Badia R, Puig-de-Vent& M, Montserrat JM. Assessment of airflow obstruction during CPAP by means of forced oscillation in patients with sleep apnea. Am J Respiv Crit Cave Med 1998; 157: 1526-1530. 35 Schlenker E, Feldemeyer F, Riihle KH. Oscillatory impedance (01) a sensitive method to detect obstruction in upper airway resistance syndrome (UARS). Eur Respiu ] 1996; 9: 197s. 36 Pitson DJ, Stradling JR. Evaluation of pulse transit time as a screening respiratory sleep study. Am ] Respiv Crit Care Med 1995; 151: A250. 37 Davies RJO, Vardi-Visy, Clarke M, Stradling JR. Identification of sleep disruption and sleep disordered breathing from the systolic blood pressure profile. Thorax 1993; 48: 1242-1247. *38 Lkvy P, P@pin JL, Mayer P, Wuyam 8, Veale D. Management of simple snoring, upper airway resistance syndrome and moderate sleep apnea syndrome. Sleep 1996; 19: SlOl-SllO. 39 Schwartz AR, Gould AR, Schubert N, et al. Effects of weight loss on upper airway collapsability in obstructive sleep apnea. Am J Respiv Dis 1991; 144: 494-498. 40 Braver HM, Bloch AJ, Perri MG. Treatment for snoring: combined weight loss, sleeping on side and nasal spray. Chest 1995; 107: 1283-1288. 41 Rauscher H, Formanek D, Zwick H. Nasal continuous positive pressure for non-apneic snoring? Chest 1992; 101: 903-909. 42 Krieger J, Kurtz D, Petiau C, Sforza E, Trautmann D. Long term compliance with CPAP therapy in obstructive sleep apnea patients and in snorers. Sleep 1996; 19: S136-5143. 43 Pkpin JL, Veale D, Mayer P, Bettega G, Wuyam B, L&y P. Critical analysis of the results of surgery in the treatment of snoring, upper airway resistance syndrome (UARS), and obstructive sleep apnea (OSA). Sleep 1996; 19: S90-SlOO. 44 Newman JP, Clerk AA, Moore M, Utley DS, Terris DJ. Recognition and surgical management of the upper airway resistance syndrome. Laryngoscope 1996; 106: 1089-1093. 45 Utley DS, Shin EJ, Clerk AA, Terris DJ. A cost-effective and surgical approach to patients with snoring, upper airway resistance syndrome, or obstructive sleep apnea syndrome. Laryqoscope 1997; 107: 726-734. surgery for treating obstructive sleep apnea. Sleep 46 Sher AE, The role of maxilomandibular 1996; 19: S88-S89.
Reviews, Vol. 3, No. 1, pp 5-21, 1999
SLEEP MEDICINE pGj
REVIEW ARTICLE
Upper airway J. M . Montserrat
resistance
syndrome
and J. R. Badia
Servei de Pneurnologia i Al.ltrgia Respirathia, Departament de Medicina, Hospital Clinic, Facultat de Medicina de la Universitat de Barcelona, Barcelona, Spain
This article reviews the clinical picture, diagnosis and management of the upper airway resistance syndrome (UARS). Presently, there is not enough data on key points like the frequency of UARS and the morbidity associated with this condition. Furthermore, the existence of UARS as an independent sleep disorder and its relation with snoring and obstructive events is in debate. The diagnosis of UARS is still a controversial issue. The technical limitations of the classic approack to monifor airflow with tkermistors and inductance pletkysmograpky, as well as the lack of a precise definition of kypopnea, may have led to a misinterpretation of UARS as an independent diagnosis from the sleep apnea/hypopnea syndrome. The diagnosis of tkis syndrome can be missed using a conventional polysomnograpklc setting unless appropriate techniques are applied. The use of an esophageal balloon to monitor inspiratory effort is currently the gold standard. However, other sensitive methods suck as the use of a pneumotackograpk and, more recently, nasal cannula/pressure transducer systems or on-line monitoring of respiratoy impedance witk the forced oscillation technique may provide other interesting possibilities. Recognitiofl and characterization of tkis subgroup of patients within sleep breathing disorders is important because tkey are symptomatic and may benefit from treatment. Management options to treat UARS comprise all those currently available for sleep apnea/kypopnea syndrome ISAHS). However, the subset of patients classically identified as UARS that exhibit skeletal craneo-facial abnormalities might possibly obtain further benefit from maxillofacial surgery. Key words: obstructive
sleep apnea, OSAS, SAHS, UARS, flow limitation
In the last decades the existence of sleep disordered breathing, its clinical consequences and its high prevalence have been progressively recognized and can be considered a major health problem [l]. Initially, attention focused on the sleep apnea through studies of the classical picture of the Pickwick syndrome that involved a group of obese patients with respiratory and cardiovascular co-morbidity that presented with a large number of apneas during sleep. However, progressively, our concept of sleep disordered breathing has substantially changed since the description of the Pickwickian syndrome. The spectrum of sleep disordered breathing is today much broader and ranges from non-apneic situations, such as simple snoring and hypopnea, to obstructive sleep apnea. In fact, with the description by the group of Douglas, that airflow reduction or hypopnea due to partial collapse promoted the same disturbances as complete
Correspondence to be addressed to: J. M. Montserrat, Servei de Pneumologia i Al.krgia Respiratbria, Hospital Clinic, Villarroel170,08036 Barcelona, Spain. e-mail: [email protected] 1087-0792/99/010005+17$12.00/0
0 1999 W.B. Saunders Company
Ltd
6
J. M. Montserrat and J. R. Badia
apnea [2], the terminology “sleep apnea/hypopnea syndrome” (SAHS) has become the most appropriate to quantify events in sleep disordered breathing. Patients with SAHS suffer repeated episodes of increased upper airway resistance with partial or complete collapse that lead to profound disturbances in sleep architecture and arterial blood gases [3,4]. Repeated inspiratory efforts occur during obstructive events until arousal ensues and airway patency is restored [5]. Repeated arousals and sleep fragmentation are responsible for subsequent daytime sleepiness. Increases in upper airway resistance, the main pathophysiological feature of SAHS, are not exclusive to apnea and hypopnea and may also be present in simple snoring and in other entities like the topic of this review: the upper airway resistance syndrome. In this respect, we believe that the main pathophysiological features that take place in the upper airway resistance syndrome (UARS) are similar to those in hypopnea. The obstructive events that occur in SAHS are secondary to an increased upper airway collapsibility. Indeed, in apneas the critical opening pressure, which is the minimal intraluminal pressure required to maintain upper airway patency, increases above atmospheric pressure during sleep. As a consequence, a static occlusion occurs and apnea takes place. On the other hand, during hypopneas, the intraluminal pressure is just above the critical opening pressure. In this situation, the inspiratory effort decreases intraluminal pressure below the critical opening pressure, the upper airway collapses partially and the inspiratory flow becomes limited. Figure 1 shows three examples of the spectrum of airflow obstruction ranging from complete apnea (Fig. la) to hypopnea with marked airflow limitation (Fig. lb, c). Depending on the magnitude of this dynamic upper airway obstruction ventilation may be reduced substantially (hypopnea) or slightly (UARS). These changes may not be recognized if the devices used to analyse and quantify airflow are not sensitive enough. In this context it is clear that the most widespread palliative treatment applied in SAHS, nasal CPAP, has a double function: on the one hand it prevents the static obstruction (CPAP pressure overcomes critical opening pressure) and on the other hand, CPAP should be able to compensate for the maximum inspiratory dynamic collapse, thus avoiding hypopneas and the UARS. Lugaresi has reported very high inspiratory pressures in heavy snorers below the fluttering segment [6]. Taking into account that snoring is the major symptom associated with SAHS, this author proposed a unitary explanation, an evolving continuum from snoring to obstructive events and apnea [7]. He suggested a theory of a snoring scale and “snoring disease”, in which snoring represented the stage 0 of obstructive sleep apnea syndrome. Christian Guilleminault had the merit to clarify, at least in part, the relationship between increased respiratory resistance, snoring and sleep fragmentation with daytime sleepiness providing a further insight into this complex situation. In 1982, this author provided an initial report on the effect of increased respiratory load during sleep in children with symptoms similar to that of sleep apnea [8]. Along this line he identified heavy snoring as a cause of excessive daytime sleepiness [9]. This author and co-workers reassembled the conception of sleep disordered breathing with the description of the upper airway resistance syndrome (UARS) [lO,ll]. They focussed their attention on a group of subjects with complaints of excessive daytime sleepiness (EDS) presenting with a trivial number of obstructive events as currently scored during full polysomnography. Sleep fragmentation with short repetitive arousals secondary to increased upper airway resistance in the absence of apnea and hypopnea were observed and were related to EDS. Some of the patients had maxilo-mandibular abnormalities. Reversal of sleep fragmentation and sleepiness was achieved with nasal continuous positive airway pressure (nCPAP) further supporting the evidence that
Upper airway
resistance syndrome
7
(a)
Expiration
IZI
0
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15 Time (s)
20
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1. Examples of the three different patterns of oscillatory airway impedance during respiratory events. Pattern (a) corresponds to an apnea with a corresponding persistent increase of 1Z ( o b served throughout the apnea. Patterns (b) and (c) depict two different hypopneas with minimal airflow and the corresponding intermittent patterns in 1Z I. In the first hypopnea (b), high Z values are interrupted by intermittent decreases during expiration whereas pattern (c) shows normal 1Z ( values, followed by intermittent increases during inspiration. (Reproduced with permission from Badia R. et al. Eur Respir J 1998.) Figure
abnormal upper airway resistance was responsible for the disorder. Furthermore, the relation between snoring, UARS and SAHS has become even more intriguing with the description of UARS in subjects that do not snore [11,12]. To date, the frequency of UARS in snorers and non-snorers as well as the morbidity associated with this condition are still unknown. Depending on the methodology applied to diagnose the syndrome, UARS may be significantly under-recognized. It may even be possible that UARS is
J. M. Montserrat and J. R. Badia
8
(a)
3‘s
0.5
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-0.5
IO
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4
60
2
4
60
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4
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60
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Figure 2. (a) Actual flow measured by the pneumotachogarph (V’) for sinusoidal airflows of 1 l/s and 0.5 l/s for a square-wave flow of 0.5 l/s (peak-to-peak). (b) Thermistor signal (V’th) recorded simultaneously. (Reproduced with permission from Farre R. et al Eur Respir 1 1988.) not an independent disorder from hypopneas but, a subgroup with particular identifiable traits in the spectrum of SAHS that needs appropriate technology to be diagnosed. In fact, the use of thermistors as flow-measuring devices for detecting hypopneas has been recently questioned [13]. Farre et al. assessed the accuracy of thermistors/thermocouples as devices for detecting hypopneas in sleep studies. These authors demonstrated that the thermistors were strongly nonlinear and largely underestimated flow reductions. A 50% reduction of the real flow resulted in only an 18% reduction in the thermistor signal. The example in Figure 2 clearly shows that the thermistor is not able to accurately measure the real flow or reproduce the morphology of the inspiratory flow. Therefore, the use of thermistors to quantify hypopneas may lead to considerable underdetection of respiratory periods of increased upper airway resistance. Another technical aspect is the concept of the morphology of the inspiratory flow as a simple and easy way to detect increases in upper airway resistance. In common with other colleagues, we have introduced nasal prongs connected to a pressure transducer as a better tool to measure ventilation [14-191. This method offers two advantages: (1) if the square root of the signal is used, then the signal is reliable from the quantitative point of view; and (2) owing to the accuracy of this signal, flow limitation can be identified without the use of an esophageal balloon. Therefore, we have proved that nasal prongs are more sensitive than thermistors in quantifying ventilation [17-191. All the previous considerations suggest that UARS probably represents a subgroup of patients within sleep disordered breathing that demand a more accurate technology. Unless a sensitive monitoring methodology is used, this condition may be missed. These patients are symptomatic because they have sleep disordered breathing-related arousals, but these respiratory events are not detected by thermistors. To recognize these particular events technologies other than thermistors are needed. In most cases
Upper airway resistance syndrome
9
appropriate use of the sum of the thoracoabdominal movement, the nasal prongs or a pneumotachograph will allow in the recognition of sleep related arousals secondary to periods of upper airway obstruction, avoiding the use of an esophageal balloon. The SAHS and the UARS have common features; similar symptoms, same pathophysiology with increased upper airway resistance and large negative esophageal pressures, increased number of arousals. Finally, both conditions improve with nCPAI? However, SAHS and the UARS differ substantially in the results of the full polysomnography. Specifically, UARS presents EDS in the absence of respiratory events (as defined using thermistors) and with minimal or absent oxygen desaturation.
Definition
and clinical
picture
The initial definition of UARS included the combination of three criteria: (1) a complaint of daytime sleepiness documented or not with a multiple sleep latency test; (2) demonstration of short repetitive periods of flow limitation by monitoring esophageal pressure (Pe,); and (3) periods of increased respiratory efforts with arousal following peak negative inspiratory I’,, [ll]. Figure 3 shows an example from the original description by Guilleminault et al. [l]. Please note that increases in I’,, as well as airflow limitation are present in the cycles prior to arousal. The common clinical picture of UARS is that of a subject with prominent symptoms of excessive daytime sleepiness and a conventional polysomnographic sleep study with a trivial respiratory disturbance index (RDI). Dips in oxygen saturation are minimal and, frequently, not present at all. Unless invasive procedures are used increased respiratory efforts remain unnoticed. Daytime sleepiness, the guiding sign of UARS, is due to repeated arousals and sleep fragmentation [10,12]. Snoring, a hallmark of SAHS, is not always present. In contrast to SAHS, individuals are frequently slim. They may also exhibit mild mandible defects or evident retrognatia associated with an abnormally narrow ogival hard palate. Narrow posterior airway space at the base of the tongue in cephalometric studies has also been described as possibly a common feature [11,20,21]. Whereas SAHS is diagnosed much more frequently in males, the incidence of UARS seems to be similar in both genders. All these distinctive traits provide a characteristic profile that can help in the recognition of UARS. Although scattered, there seems to be enough information to establish a clinical picture of the syndrome. Unfortunately, solid data on the prevalence and significance of each of these features in UARS is completely missing and the diagnosis requires polysomnography (PSG) data as well as the demonstration of increased respiratory resistance leading to sleep fragmentation. UARS is still very difficult to identify and the morbidity beyond EDS related with this condition remains largely unknown. Despite the current suggestion that increased upper airway resistance may lead to systemic hypertension and cardiovascular disorders [22-241 morbidity has not been characterized. This is not surprising and is possibly related to the uncertainty of the diagnosis of UARS itself. Prospective studies that rely on more accurate definitions are needed. The question again is whether UARS has a definite identity distinct from SAHS and if it may exist in the absence of hypopneas or apneas. The methodology applied in the diagnosis of UARS is a core issue. It is possible that, in addition to the use of an esophageal balloon, new and more sensitive technologies which are available to monitor airflow obstruction, will contribute to unravel the real significance and incidence of this condition.
J. M. Montserrat and J. R. Badia
ECG
Figure 3. Original picture by C. Guilleminault et a2. of a PSG recording showing an example of upper airway resistance syndrome. Key: EEG, electroencephalogram; EMG~~,,i,l, facial muscle electromyogram; EOG, electrooculogram (right and left); ECG, electrocardiogram; Flow rneumotach, pneumotachometer to quantify airflow; I’,,, esophageal manometry to record esophageal pressure; RESP,,,, respiratory effort. Please note that increases in I’,, as well as airflow limitation are present in the cycles prior to a transient EEG arousal indicated by the solid arrowhead (Reproduced with permission from Guilleminault C. et al. Chest 1993.)
Diagnostic
strategy
The conventional PSG approach fails to recognize the UARS. Thus, the diagnosis of UARS has required monitoring of I’,, with an esophageal balloon to identify periodic increases in inspiratory effort. It seems likely that these result from increases in airway resistance secondary to airflow obstruction, although this may be subtle or limited to very short periods. Again, the methodology applied to monitor airflow appears critical. The use of an esophageal catheter to monitor inspiratory effort as an indirect measure of airflow obstruction is the gold standard. When using I’,, the most distinctive trait is not the isolated values of negative inspiratory pressure itself but the characteristic pattern of progressive fast decrease of I’,, that abruptly returns to normal, or almost normal, after a neurological arousal. However, the procedure is invasive and can
Upper airway
resistance
syndrome
11
influence the measure [25]. Other confounding issues are the interindividual variability of the values of P,, and the variability related to changes in sleep phase as well as the need to establish the range of normal values. Measurement of P,, with an esophageal catheter probably cannot be recommended as a diagnostic routine. In most laboratories changes in nasal and mouth airflow ventilation are currently detected and measured by thermally sensitive devices -thermistors[26]. Indirect parameters, such as thoracic and abdominal movements measured with bands, are also reliable [2]. Depending on the qualitative changes in the thermistor signal and thoraco-abdominal motion apneas and hypopneas are defined. However, hypopneas are still a matter of controversy. Scoring depends much on the recording technique and a precise definition of hypopnea is completely lacking [27]. In this respect, the accuracy of thermistors/thermocouples as flow-measuring devices for detecting hypopneas is far from optimal [13,28,29]. As previously pointed out, they are semiquantitative devices since the flow signal they provide is not a direct measure of actual flow. Thermistors have a very poor time response and show a critical dependence on the airflow pattern, the distance to the nose and the cross-section of the nostrils. These drawbacks do not produce major problems to score apneas. However, the use of thermistors to quantify hypopneas leads systematically to underdetection of these respiratory events. If thermistors are used we can assume that the respiratory disturbance index (RDI) in hypopneic patients is underestimated. In addition, short periods of flow limitation leading to arousal or microarousal can be completely overlooked. It is possible that if we use an esophageal catheter a substantial number of these patients may meet criteria to label them as UARS. The importance of developing a non-invasive methodology that allows precise monitoring of airflow obstruction is obvious. It is necessary to use techniques capable of detecting subtle changes in airflow. An attractive option can be the regular use of a pneumotachograph. However, to acquire a flow signal with a pneumotachograph a tight-fitting nasal or face mask is required. More recently, it has been suggested that nasal cannula or prongs connected to a pressure transducer could be a useful alternative to monitor respiratory events due to their ability to measure and quantify nasal flow [14]. The main advantage of nasal prongs is their good dynamic response when compared with thermistors. Our group conduct e d a study to evaluate if nasal prongs could improve the detection of respiratory-related arousals and respiratory events [18]. Nasal prongs proved to be much more sensitive than thermistors and thoraco-abdominal bands and the detection of respiratory events increased significantly (from 62% with thermistors to 96% with nasal prongs) In addition, the number of false positives related to mouth expiration was reasonable (3%). Figure 4 is a good example of the poor accuracy of thermistor to recognize respiratory events compared with nasal prongs. We also found that nasal prongs were easily tolerated during sleep studies even when applied together with thermistors. An additional advantage of these devices is their ability to detect airflow characteristics due to their excellent dynamic response. The upper airway behaves as a Starling resistor and, in conditions of increased resistance due to partial collapse, inspiratory airflow has a nonlinear relation with inspiratory esophageal pressure. Increases in inspiratory effort do not generate a further increase in flow. When an adequate measurement of actual flow is available it has been shown that limitation in the inspiratory waveform is correlated with elevated upper airway resistance and increased esophageal pressure [15,16]. Partial airflow limitation can be identified by a flattened morphology of the inspiratory flow contour. Figure 5 (a-c) show the higher accuracy of nasal prongs to recognize respiratory events and their ability to provide
J. M. Montserrat and J. R. Badia
C4-Al
O-A EMG-GG
EMG legs
.__._-___I
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Figure 4. A representative polysomnographic view of the behavior of nasal prongs during hypopneas. Note the poor detection of respiratory events obtained through thermistors. Respiratory events are much more clearly identified by nasal prongs. Key: EOG, electrooculogram; EMG-GG, electromyogram; ECG, electrocardiogram. information on flow limitation. Please note that in these examples the thermistor is completely unable to detect the changes that take place in ventilation. Figure 6 (a) and (b) shows the accuracy of nasal prongs to detect airflow limitation and the relation with esophageal pressure and upper airway resistance. Nasal prongs/pressure transducer systems have additional advantages, as the detection of snoring (Fig. 5a) or a more precise follow-up of the time-course of respiratory events within the breathing cycle. Nevertheless, nasal prongs may present some problems, for example the inability to detect mouth expiration or the possible occurrence of physiological flow limitation in normal subjects [30]. The role of nasal prongs in everyday work in the sleep laboratory is still not well defined. Criteria to score respiratory events or definition of physiological changes in this signal need further research and standardization. However, these systems provide a valuable and complementary diagnostic tool. We have already included the use of nasal prongs in our routine diagnostic setting. In our experience since we have implemented this signal, the number of patients that may fit in the definition of UARS has dramatically decreased. This further supports the concept that UARS may be, at least in part, a “technical” syndrome directly related to a suboptimal methodology to measure and quantify airflow obstruction. Another diagnostic approach to non-apneic situations with subtle changes in respiratory variables is to monitor upper airway impedance by means of the forced oscillation technique. The forced oscillation technique (FOT) provides a non-invasive method to assess and quantify airway obstruction. It consists in superimposing on the spontaneous breathing a small pressure oscillation through a nasal mask attached to the patient [31]. Respiratory impedance (Z) is derived on-line from pressure and flow signals recorded at the nasal mask. The potential applicability of FOT to assess airway obstruction in SAHS
Upper airway
resistance syndrome
13
has been confirmed in a model study [32]. In this preliminary work the amplitude of the impedance ( 1Z ( ) measured by FOT was found to be an accurate index of overall airflow obstruction. Our group has also evaluated the suitability and accuracy of the technique in diagnostic sleep studies in SAHS [33]. Figures 1 and 7 are examples of the clinical application of this technique to assess airflow obstruction both in apnea and hypopnea. The clinical applicability of FOT to assess airflow obstruction in real time during CPAP treatment has also recently been demonstrated in a limited number of patients with recording of I’, [34]. Figures 8 and 9 show the ability of FOT to recognize airflow obstruction during CPAI? This technique proved to be sensitive to even slight increases in upper airway resistance demonstrated by esophageal catheter in patients treated with slightly suboptimal CPAP and can improve detection of respiratory events inpatients with suspected UARS [35]. In our experience continuous measurement of airflow obstruction by FOT provides a very rational non-invasive approach to monitor airway mechanics and may allow a better characterization of non-apneic sleep disordered breathing. Pulse transit time (PTT) [36] and beat to beat blood pressure profile [36] can also be considered. These promising methods may detect increased respiratory effort and neurological activation (either arousal, microarousal or autonomic arousal), the two main components involved in the pathophysiology of UARS. However, further research on these procedures is needed to assess sensitivity and specificity in the detection of increased upper airway resistance before they can be introduced in standard diagnostic procedures.
Treatment UARS is still an undefined clinical situation. The main end points of treatment for abnormal increases of airway resistance should be to relieve symptoms and improve quality of life. The aim in treatment should be to reduce morbidity and mortality. However, in non-apneic situations as the classical description of UARS associated morbidity and mortality are far from determined. From a clinical perspective, treatment of increased upper airway resistance should alleviate snoring and daytime somnolence and, probably, the existence of associated cardiovascular morbidity should be considered in the final decision. Management options available to treat UARS comprise all those currently available for SAHS including weight loss, sleep posture, oral appliances, conventional CPAP and surgical procedures [38]. The first step in the management of these patients should possibly be to test general measures of weight loss and sleep positional treatment. There are no reliable data concerning weight loss and UARS. Although most patients are not obese, weight loss has a strong influence on snoring and upper airway collapsibility [39] and a first therapeutic attempt must be made. Positional treatment seems to have a higher impact on frequency and intensity of snoring, related with upper airway resistance, than on RDI itself [40] and should possibly be tested in combination with weight loss in this population. Dental malocclusion is a common feature in UARS. Oral appliances, in particular mandibular advancing devices, seem a good option to counteract increased upper airway resistance. However, there are no data available on this at the present time. CPAP must also be considered. Reversal of sleep fragmentation and daytime sleepiness is achieved. In our experience subjects with UARS appear to require a lower pressure than those with more severe obstructive events. However, there is some evidence suggesting that the compliance with CPAP could be unsatisfactory in these
J. M. Montserrat
14
5(a)
Thermistor
SaOz
5(b) EOG-I EOG-D
and J. R. Badia
Upper airway resistance syndrome
15
5(c) EOG
--4--------p.
Snore
Figure 5. Three representative polysomnographic views of the behavior of nasal prongs during hypopneas. Note the null detection of respiratory events obtained through thermistors. A respiratory event could be missed if thermistor were the sole method used to detect airflow. The nasal prongs show a limited inspiratory flow (a, b), very short in (c), and an inspiratory vibration (a) that corresponds to snoring, ending with an arousal.
patients although results from different groups are at variance in this point [41,42]. A therapeutic trial with CPAP is a good choice in those symptomatic patients that do not improve on conservative treatment. Finally, surgical management must be considered. Published studies on surgery for UARS present general limitations that have been described in detail elsewhere [43]. Simple snorers and non-apneic subjects with increased upper airway resistance syndrome are more likely to obtain benefit from surgery than other patients. However, information on objective results is particularly scarce in this group and further studies are most needed [38,43]. In UARS skeletal abnormalities that may increase upper airway resistance are often present. Dental malocclusion and elevated ogival hard palate as well as a narrow posterior airway space seem to be, in our experience, common findings. Maxillofacial surgery aimed towards correcting upper airway skeletal anatomic abnormalities yield the best results of surgery in the treatment of SAHS and is probably the most rational approach for symptomatic patients in this subgroup [44-46]. Selection criteria and elucidation of predictive factors for this type of surgery need to be established.
Conclusion In our opinion the group of patients defined as having the upper airway resistance syndrome form a particular population within the spectrum of SAHS but not an
J. M. Montserrat and J. IL Badia
16 (a)
Nasal prongs
Thoracoabdominal
Esophageal
bands
pressure
(b)
EMG
EKG
Nasal prongs
P,,, (cmH@) -30OCfl Sa02
Figure 6. Representative tracings of respiratory variables and esophageal pressure during a sleep study. Note that periods of flow limitation correspond to high inspiratory esophageal pressure. Conversely, when esophageal pressure is low [during an arousal in (b)] the inspiratory flow morphology is rounded.
Upper airway resistance syndrome
Figure 7. A representative standard compressed polysomnographic recording (6 epoch, 3 min) with oscillatory impedance 1Z 1 added at the bottom. Note that 1Z 1 shows low values during arousal and increases during the apnea periods. The last event on this tracing corresponds to hypopnea. This increase shows cyclical variation before the onset of each apnea and during an hypopnea (last event in this figure). Definition of abbreviations according to channels: Electrooculogram (EOG) (channel #1 and #2); C4-Al and C3-A2 (electroencephalogram channels #3 and #4); chin electromyogram (EMG-GG) (channel #5); flow by pneumotacograph (channel #6); Effort: thoracicabdominal bands (channels #7 and #8); (Reproduced with permission from Badia et al. Eur Respir J 1988.) independent sleep disorder. In this sense, the real significance of UARS has probably been overestimated due to limitations of the methodology used to monitor airflow. This technical deficiency underlies the definition of this condition itself. Therefore, introduction of more sensitive devices will have a direct impact on the frequency and signification of this diagnosis. However, we do believe that there is a specific population, classically identified as UARS, that shares some features uncommon to the rest of subjects with SAHS. Possibly the most representative characteristic of this subgroup is the presence of a subtle respiratory dysfunction that is enough to generate arousal and sleep fragmentation and, therefore, daytime symptoms. Our knowledge of the functional properties of the upper airway that determine the appearance of snoring, hypopneas or apneas is still very limited. Furthermore, not much is known about the individual threshold at which increased upper airway resistance can elicit arousal, microarousal or autonomic arousal. Differences in these issues could explain the description of UARS without snoring in some cases or upper airway collapse at low inspiratory pressures in other subjects. A consensus on diagnostic methodology considering the new available technologies is required. A more accurate technical approach to sleep disordered breathing, in particular in non-apneic situations, will probably lead to a reconsideration of our current nosological definitions.
J. M. Montserrat and J. R. Badia
SaO,
Figure 8. A representative standard compressed polysomnographic recording obtained during CPAP titration with oscillatory impedance (Z ( added at the bottom. (Z ( shows intermittent increases at suboptimal CPAP corresponding with a limited inspiratory airflow morphology. Note that when CPAP is increased the shape of the inspiratory flow wave becomes rounded and values of 1Z 1 are similar to those obtained during awake normal breathing.
CPAP = 4 cmHzO
10
20
CPAP = 8 cmHzO
30
0
10 20 Time (s)
CPAP = 12 cmHzO
30 0
10
20
30
Figure 9. Breathing flow (V’), esophageal pressure (P,J and respiratory resistance (R,,) measured by the FOT in -a patient at different levels of CPAl? (Reproduced with permission from Navajas D. et al. Am J Respir Crit Cure Med. 1988.)
Upper airway resistance syndrome
19
Practice Points Upper airway resistance syndrome &JARS) is currently defined as the combination of: 1. excessive daytime sleepiness. 2. periods of increased respiratory effort terminating abruptly with an arousal without a major decrease in airflow when is measured by thermistor, and 3. without a significant fall in oxygen saturation The use of thermistors to asses flow may lead to considerable underdetection of respiratory events. Nasal prongs or a pneumotachograph or even the sum of thoracoabdominal motion improves the recognition of sleep related arousals secondary to periods of upper airway obstruction, avoiding the use of an esophageal balloon in many cases. When these signals are implemented in routine practice, hypopneas are accurately recognized and the number of patients diagnosed of UARS decreases dramatically. New more sensitive technologies available to monitor airflow obstruction will contribute to uncover the real significance and incidence of UARS. Research Agenda 1. Morbidity associated with non-apneic sleep disorders has not beeri established. Prospective studies that rely on more accurate definitions are needed 2. There is a specific population, classically identified as UARS, that shares some features uncommon to the rest of subjects with SAHS. A better characterization is needed. 3. Knowledge of the functional properties of the upper airway that determine the appearance of snoring, hypopneas or apneas and the individual threshold at which increased upper airway resistance can elicit arousal, microarousal or autonomic arousal is still very limited. 4. Long-term compliance with CPAP therapy irt patients with non-apneic sleep disorders needs further evaluation. 5. Selection criteria and elucidation of predictive factors for maxillo-facial surgery need to be established.
Acknowledgements This study was supported by Fondo de Investigaciones Sanitarias (FIS) no. 97/422 and FUCAP 97. References 1 Phillipson EA. Sleep apnea. A major public
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